Male Hypogonadism

Male Hypogonadism
Presentation lecture by:Michael Jakoby, MD/MA
Clinical Associate Professor of Medicine
Chief, Division of Endocrinology


Case study
Definition
Decrease in one or both of the two major functions of the testes.
Low/low nl
Gonadotrope failure
Secondary
Elevated
Testicular failure
Primary Sperm count
Testosterone
Gonadotropins
Pathology
Hypogonadism
Gonadal Axis
Male Gonadal Function
Male Puberty
Clinical Features
Postpuberty
Prepuberty
Micropenis
3rd trimester
Incomplete virilization
1st trimester
Effects
Age
Screening for Androgen Deficiency

* Infertility
* Sellar mass, radiation, or surgery
* Osteoporosis or low trauma fracture
* HIV-associated weight loss
* ESRD
* COPD (moderate to severe)
* Type 2 diabetes mellitus
* Medications that effect testosterone production
o Glucocorticoids
o Opiates
o Ketoconazle
The Endocrine Society recommends against screening for androgen deficiency in the general population
History

* Symptoms onset
* Testicular size
* Breast enlargement
* Behavioral abnormalities
* Chemotherapy or radiation therapy
* Alcoholism
* Visual field defects
* Medications

Examination

* Testicular size
* Pubic hair
* Gynecomastia
* Muscle mass
* Body proportions
* Fundoscopy & visual fields screening

Laboratory Testing
Secondary hypogonadism
Low sperm ct
Primary hypogonadism
Elevated
Low sperm ct
Low/low nl
Diagnosis
Gonadotropins (LH/FSH)
Semen analysis
Testosterone
Testosterone Measurements
Testosterone in Obese Men
Testosterone Secretion:
Comparison of Young and Elderly Men
Standard Semen Analysis
DDx: Primary Hypogonadism

* Klinefelter’s syndrome
* Gonadotropin receptor mutations
* Cryptorchidism
* Androgen biosynthesis disorders
* Varicocele
* Congenital anorchia
* Mumps orchitis
* Radiation
* Antineoplastic drugs
* Ketoconazole
* Glucocorticoid excess
* Trauma
* Testicular torsion
* Autoimmune orchitis
* Cirrhosis
* Chronic renal failure
* HIV infection
* Idiopathic
Congenital
Acquired
DDx: Secondary Hypogonadism

* Isolated hypogonadotropic hypogonadism
* Kallman’s syndrome
* DAX1 mutation
* GPR 54 mutation
* Leptin or leptin receptor mutations
* Gonadotrope receptor mutations
* Hypopituitarism
* Hyperprolactinemia
* Androgen therapy
* GnRH analog therapy
* Glucocorticoid therapy
* Critical illness
* Chronic illness
* Diabetes mellitus
* Opiates
* Pituitary mass lesions
* Infiltrative diseases
* Sellar surgery
* Sellar radiation
Evaluation of Men with Androgen Deficiency

Confirmed low testosterone
Check LH+FSH (SA if infertility)
High gonadotropins – 1o
Low/low nl gonadotropins – 2o
Karyotype
Prolactin, other pituitary hormones, iron studies, sella MRI
Klinefelter’s Syndrome
Gonadal Manifestations of Klinefelter’s Syndrome
Decreased penis length
Decreased axillary hair
Gynecomastia
Decreased sexual function
Increased gonadotropins
Decreased facial hair
Low testosterone
Azoospermia
Decreased testicular length
Abnormal testicular histology
Frequency (%)
Abnormality

Testosterone Replacement
* Primary goal is to restore testosterone levels to the laboratory reference range
* Prescribe only for patients with confirmed hypogonadism
* Role in “treating” decline in testosterone levels with aging uncertain
* Multiple preparations
o Oral
o Intramuscular
o Transdermal
o Buccal
Oral Testosterone Preparations

* Alkylated testosterone more slowly metabolized by liver than native testosterone
* May not induce virilization in adolescents
* Untoward effects
+ Cholestatic jaundice
+ Peliosis hepatis
+ Hepatocellular carcinoma

Intramuscular Testosterone

* Enanthate and cypionate esters of testosterone
* Lipophilic, leading to sustained release from muscle depots
* Side effects related to dosing or administration
* Regimens of 100 mg q wk to 300 mg q 3 wks acceptable
* Goal is a mid-cycle level near the middle of the laboratory reference range

Transdermal Testosterone

* Patch (Androderm)
o Apply to skin of upper arms and torso
o Delivers 5 mg testosterone/24 hr in continuous manner
o Approximately 1/3 of patients develop significant contact dermatitis
* Gels (Androgel, Testim)
o Apply to skin of upper arms and torso
o Usually dosed as 5.0 g or 10.0 g of gel to deliver 50 mg or 100 mg testosterone, respectively in a continuous manner
o Reports of contact dermatitis and gel odor uncommon

Desirable Effects of Testosterone Therapy
* Virilization (incompletely virilized men)
* Increased libido and energy
* Improved erectile function?
* Increased muscle mass and strength (8-10 wks)
* Increased bone mass (full effect ~ 24 mo)

Untoward Effects of Testosterone Therapy

* Pain at injection site (IM preparations)
* Contact dermatitis (patch >> gel)
* Acne or oily skin
* Gynecomastia
* Aggressive behavior (adolescents)
* Short stature (adolescents)
* Increased prostate volume/PSA
* Urinary retention (BPH exacerbation)
* Sleep apnea
* Erythrocytosis

Contraindications to Testosterone Therapy

* Very high risk of adverse outcomes
o Prostate cancer
o Breast cancer
* High risk of adverse outcomes
o Undiagnosed prostate nodule
o Unexplained PSA elevation
o BPH with severe urinary retention
o Erythrocytosis
o NYHA Class III or IV heart failure
Pre-treatment Screening

* Digital rectal exam
* History of urinary retention (urodynamic studies, bladder US PRN)
* History of sleep apnea symptoms (polysomnography PRN)
* PSA (urology referral if > 4 ng/mL)
* CBC

Treatment Monitoring

* Serum testosterone
o IM testosterone: midpoint between injections, level near middle of reference range
o Patch: 3-12 hrs after applying new patch
o Gel: timing not critical
o Buccal pellet: immediately before or after new pellet
* Prostate
o DRE @ 3 months, then annually
o PSA @ 3 months, then annually
o Prostate biopsy if PSA > 4 ng/mL, PSA increases by > 1.4 ng/mL in 12 months, or PSA velocity > 0.4 ng/mL/yr
* Red cell mass
o CBC at 3 months, then annually
o If Hct > 54%, stop therapy, monitor for return to reference range, then resume therapy at a lower dose

Summary
Male Hypogonadism.ppt

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Male-Female Binary and Sex Determination

Male-Female Binary and Sex Determination

Gender/Sex/Sexuality Diversity
Usual Sex Chromosomes
XXXXY Chromosomes
More than one X = Barr Bodies
Only one X is functional in any one cell
The other(s) fold up and get out of the way at the edge of the nuclear membrane
These “extra” X’s can be seen in the microscope and counted

Do Chromosomes Matter?

* Yes, but …
* Does XX make a female?
* Does XY make a male?
* Is XO male or female?
* 1/1666 not XX or XY

Do Gonads Matter?

* Yes, but….
* Do ovaries make a female?
* Do testes make a male?
* What do ovo-testes make?

Do Hormones Matter?

* Yes, but …
* XY chromosomes
* Cells can’t “read” male hormone signals
* “Feminine” development
* “Male” or “Female”?

Conventional Sex/Gender Variables

Prefers females
Prefers males
Sexual orientation
Masculine
Feminine
Gender role
Gender identity
Assigned gender
Prostate, testes, penis, scrotum
Uterus, ovaries, clitoris vagina
Anatomy
testosterone
Estrogen/ progesterone
Hormones
Testes
Ovaries
Gonads
XY
XX
Chromosomes

MALE
FEMALE
VARIABLES
Chromosomes and Sex Determination
Gonadal Development [regulated by genes]
Embryology of internal reproductive organs
Sex Chromosomal Variation in Humans
Turner’s Syndrome: X0
Klinefelter’s Syndrome: XXY
Androgen Insensitivity or “Testicular feminization”
Baby Girl or Baby Boy?
Hormonal Virilization
Congenital Adrenal Hyperplasia
Sex determining Region of Y (SRY)
Suppression of Female Development
Some Questions….

* How can the mechanisms that lead to sexual differentiation vary?
* What might you predict might be some outcomes of such variations?
* How would you apply gender/sex based rules/laws in cases of non-standard chromosomes?

Male-Female Binary and Sex Determination.ppt

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Common Genetics Problems in Pediatrics

Common Genetics Problems in Pediatrics
Presentation lecture by:Shannon Browning MD

Klinefelter Syndrome

* Occurs in approximately 1 in 1000 births
* 80% have the classic 47,xxy karyotype, with 10 % having 46,XY/47XXY mosaicism and another 10% having multiple x or Y chromosomes
* Results from nondisjunction and is often associated with advanced maternal age
* Rarely diagnosed before the onset of puberty
* Most children with KS present initially with behavior problems , abnormal puberty or infertility issues
* Typically taller than average and increased carrying angle and a relatively wide pelvis
* 30% will develop gynecomastia during in puberty
* 50% of children have speech delays and 25% have motor
* All affected males are infertile, although there are rare cases of fertility

Sickle Cell Disease

* Results from a single genetic mutation in which a nucleotide in the coding sequence of a beta-globin gene is mutated from adenosine to thymidine
* This mutation occurs in the middle of the triplet that codes for normally glutamic acid as the 6th AA of the beta-chain of hemoglobin. The single base change substitutes Valine for glutamic acid.
* The resulting mutated hemoglobin has decreased solubility and abnormal polymerization properties
* If only 1 beta-globin gene is mutated= heterozygous state which is referred to as sickle cell trait
* If both genes are mutated resulting in homozygous state and called sickle cell anemia or sickle cell disease.
* Prenatal testing for sickle cell has improved significantly over the past 2 decades.
* The newborn with sickle cell disease is not anemic initially because of the protective affects of elevated fetal hemoglobin. Hemolytic anemia develops over the 1st 2-4mo.
* Chorionic villus sampling can be performed as early as 9 wks gestation making it an earlier alternative to amniocentesis.

Teratogens

* Accutane embryopathy is associated with embryonic exposure to isotretinoin beyond the 15th day after conception and through the end of 1st trimester
* Isotretinoin is a vitamin A derivative that is administered orally and used for the treatment of cystic acne
* It impedes the normal neural crest migration in the developing embryo.
* This disruption in the migration of the neural crest cells leads to defects in the central nervous system, severe ear anomalies, conotruncal heart defects and thymic abnormalities
* Alcohol can cause all the above mentioned abnormalities with the exception of thymus abnormalities
* Warfarin embryopathy is a recognizable pattern of malformation. Warfarin acts as an anticoagulant because it is a vitamin K antagonist. It prevents the carboxylation of gamma-carboxyglutamic acid which is a component of osteocalcin and other vit K dependent bone proteins.
* The critical period of exposure is between 6-9 weeks.

Down’s Syndrome

* 95% of all those affected with DS have trisomy of the chromosome 21
* 90-95% of these cases are due to maternal meiotic error with 75% occurring in meiosis I. 3-5% are due to paternal meiotic errors and the remainder are due to mitotic nondisjunction
* Recurrence risk estimates are based on empiric data
* The overall recurrence risk for having a child with any trisomy is approx 1% added to the mother’s age-related risk. As a woman ages the age related risk exceeds the recurrence risk

Turner Syndrome

* The two most common features in girls with TS is short stature and gonadal dysgenesis. It should be suspected in any girl of short stature with unknown cause.
* Estimated that 1 in 2500 girls are affected
* Linear growth velocity varies: from birth to 3 yrs it is normal, from 3-12 yrs velocity decreases, and after age 12 it decelerates even further.
* Most affected girls have a 45,X karyotype
* Diagnosis is based on chromosomal analysis

Neurofibromatosis Type I

* Occurs in 1 in 3000 to 1 in 4000 lives births and is unrelated to gender, ethnicity or geographic location
* Autosomal dominant condition
* 50% of cases are spontaneous mutations in the gene that codes for neurofibromin on chromosome 17.
* Males and females are equally affected
* The recurrence risk to offspring of an affected individual is 50%
* This gene abnormality shows full penetrance
* Café au lait macules (CALMs) are uniformly pigmented flat spots that range in size from a few mm to as much as 30cm in adults. CALMs increase in size in proportion to growth.
* One or two CALMs are common more than 6 raises the concern about NF-1
* Of children who present with 6 or more CALMs 89% meet the diagnostic criteria for NF-1 within 3 years.

Angelman Syndrome

* Affected children are normal at birth
* They experience global developmental delay, but speech is affected most. Most children will never speak
* They laugh frequently and have an ataxic gait and often hold their elbows away from their bodies.

Common Genetics Problems in Pediatrics.ppt

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